Immunotherapy plus DDR inhibitors may prime SCLCs for better response

By Liz Meszaros, MDLinx
Published April 12, 2019

Key Takeaways

Combining olaparib, a poly ADP-ribose polymerase (PARP) inhibitor, with DNA damage repair (DDR) inhibitors may bring about a rapid immune response and sensitize previously resistant small-cell lung cancer (SCLC) cells to immunotherapy, according to preclinical results from researchers at the University of Texas MD Anderson Cancer Center, Houston, TX. They published their findings in Cancer Discovery.

“While the use of immunotherapy has revolutionized the way we treat lung cancer, we find that [SCLCs] can escape the immune system very effectively, so we see a much lower response rate,” said corresponding author Lauren Averett Byers, MD, associate professor, Department of Thoracic Head and Neck Medical Oncology, MD Anderson. “However, we want to do a lot better for our patients, and we think there’s a lot of room for further improvement.”

In the United States, SCLC—one of the most aggressive types of cancer—accounts for roughly 15% of all diagnosed lung cancers, and affects nearly 30,000 patients annually. Chemotherapy has been the standard treatment for advanced SCLC for the past 30 years. Recurrence in these patients, however, is common, and they have an average survival of only about 12 months. The advent of immunotherapy used in combination with chemotherapy offered only minimal benefits.

In laboratory experiments, Dr. Byers and colleagues had previously shown that using PARP and checkpoint kinase 1 (CHK1) inhibitors to block DDR pathways—which are highly active in SCLCs—was effective against SCLC.

“Therefore, we predicted that if we combined PARP inhibitors or other drugs that cause DNA damage with immune therapies, we might see a much greater response to the immune therapy,” said Dr. Byers. “We found that if we added either PARP or CHK1 inhibitors to immunotherapy, we saw a dramatic shrinkage of tumors. In fact, in some cases, the tumors disappeared completely.”

Dr. Byers and colleagues found that an anti-programmed death-ligand 1 (PD-L1) immune checkpoint inhibitor combined with either prexasertib (a CHK1 inhibitor) or olaparib brought about significant tumor regression in murine models of SCLC in which immunotherapy had no effects. Further, they found that the immunotherapy/PARP inhibitor combination resulted in complete regression in all mice in 1 week. The immunotherapy/CHK1 combination therapy caused complete regression in 60% of the mice.

In this model, they observed that the stimulator of interferon genes (STING) pathway, which detects signs of viral or bacterial infection, controlled the immune response that was activated by the DDR inhibitors, and led to increases in immune cells in tumors. Specifically, chemokine levels including CXCL10 and CCL5 were increased, and prompted activation of cytotoxic T-lymphocytes. Further, the DNA damage caused the STING pathway to mount a response and activate the immune system, priming SCLC cells for a response to immunotherapy.

“I think the results from this study are really compelling because of the dramatic activity that we saw with the combination of adding a targeted therapy to immune therapy,” said Dr. Byers. “I think our findings can be rapidly translated into the clinic for our patients and also to other cancer types,” she concluded.

Dr. Byers and colleagues hope to begin new studies to investigate the combination of PARP inhibitors and immunotherapy in patients with SCLC. They also anticipated that this combination may be effective in treating other cancers characterized by increased DNA, including BRCA-mutant breast and ovarian cancers.

This study was supported by MD Anderson’s Lung Cancer Moon Shot program, the National Cancer Institute, the Lung Cancer Research Foundation, the University of Texas Southwestern Medical Center and MD Anderson Lung SPORE, the MD Anderson Small Cell Lung Cancer Working Group, the Abell-Hanger Foundation Distinguished Professorship, the MD Anderson Physician Scientist Award, the R. Lee Clark Fellowship funded by the Estate of Jeanne F. Shelby, the Rexanna’s Foundation for Fighting Lung Cancer, and the Elsa U. Pardee Foundation.

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